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Hereditary angioedema type III (estrogen-dependent)
report of three cases and literature review
*Angioedema hereditário tipo III (estrógeno-dependente): relato de três casos
e revisão da literatura
Amanda Rodrigues Miranda1
Dominique Vilarinho Sabbag1
Patrícia Karla de Souza4
Ana Paula Fusel de Ue2
Wellington de Jesus Furlani3
Osmar Rotta5
DOI: http://dx.doi.org/10.1590/abd1806-4841.20131818
Abstract: In this article, three cases of hereditary angioedema (HAE) type III (estrogen-dependent or with nor-mal C1 inhibitor) are reported. The HAE was initially described in women of the same family in association with high-leveled estrogenic conditions such as the use of oral contraceptives and pregnancy. There is no change in the C1 inhibitor as happens in other types of hereditary angioedema, and mutations are observed in the encod-ing gene of the XII factor of coagulation in several patients. The current diagnosis is mainly clinical and treat-ment consists in the suspension of the triggering factors and control of acute symptoms. A brief review of physio-pathology, clinical features, genetic alterations and treatment are also presented.
Keywords: Angioedemas, hereditary; Estrogens; Hereditary angioedema type III; Therapeutics
Resumo: Neste artigo são relatados três casos de angioedema hereditário do tipo III (estrógeno-dependente ou com inibidor de C1 normal), que foi inicialmente descrito em mulheres da mesma família, em associação com condições de alto nível estrogênico, como uso de anticoncepcionais orais e gravidez. Não há alteração do inibi-dor de C1, como acontece nos outros tipos de angioedema hereditário, e são observadas mutações no gene codi-ficador do fator XII da coagulação em várias pacientes. O diagnóstico atualmente é eminentemente clínico e o tratamento consiste na suspensão dos fatores desencadeantes e controle dos sintomas agudos. Também é apre-sentada breve revisão da fisiopatogenia, quadro clínico, alterações genéticas e tratamento.
Palavras-chave: Angioedemas hereditários; Angioedema hereditário tipo III; Estrogênios; Terapêutica
Received on 16.04.2012.
Approved by the Advisory Board and accepted for publication on 16.08.2012.
* Study carried out at the Department of Dermatology, School of Medicine - Federal University of São Paulo (EPM-UNIFESP) - São Paulo (SP), Brazil. Financial Support: None
Conflict of Interest: None
1 Dermatologist. Medical Residency in Dermatology by the Federal University of São Paulo (EPM-UNIFESP). Collaborator’s Medical Group of Environmental Immuno Dermatosis Department of Dermatology, Federal University of São Paulo (EPM-UNIFESP) - Sao Paulo (SP), Brazil.
2 Dermatologist. Master of Dermatology by the Federal University of São Paulo (EPM-UNIFESP) - São Paulo (SP), Brazil.
3 Dermatologist. Medical Residency in Dermatology by the Federal University of São Paulo (EPM-UNIFESP). Collaborator’s Medical Group of Environmental Immuno Dermatosis Department of Dermatology, Federal University of São Paulo (EPM-UNIFESP) - Sao Paulo (SP), Brazil.
4 Dermatologist. Master in dermatology by the Federal University of São Paulo (EPM-UNIFESP) - São Paulo (SP), Brazil. Medical contributor and coordinator of the Group of Environmental Immuno Dermatosis Department of Dermatology, School of Medicine - Federal University of São Paulo (EPM-UNIFESP) - São Paulo (SP), Brazil.
5 Associate Professor, Department of Dermatology, Federal University of São Paulo (EPM-UNIFESP). - Lecturer responsible for Group of Environmental Immuno Dermatosis Department of Dermatology, School of Medicine - Federal University of São Paulo (EPM-UNIFESP) - São Paulo (SP), Brazil.
INTRODUCTION
Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent episodes of swelling of the skin and / or mucous, which can also affect the gastrointestinal tract and upper airways in a severe way.1The crisis does not respond to
antihista-mines, corticosteroids or adrenaline and usually dis-appear spontaneously within 12-72 hours. There is a mutation in the gene that encodes the C1 inhibitor of the complement factor (INHC1), inducing a reduction in its synthesis (type I HAE) or the formation of a dys-functional protein (type II HAE). In 2000, a new sub-type of HAE was described, which is clinically indis-tinguishable from the others, predominantly in women, in which the INHC1 is normal.2The new
dis-order was called hereditary angioedema type III, estrogen-dependent hereditary angioedema or hered-itary angioedema with normal C1 activity (type III HAE). There is a verifiable association with this type of hereditary angioedema and situations where increased levels of estrogen occur such as the use of oral contraceptives and pregnancy, which are recog-nised crises factors.2-4The objective of this article is to
describe the clinical and laboratory findings of three cases of this new type of HAE as well as briefly reviewing existing literature on the physiopathology, clinical features, genetic alterations, diagnosis and treatment.
REPORT OF THE CASES
1. Female patient, 35 years old, married, doctor, reported crisis of intense facial swelling for nine years, always attacking the lips. At the beginning the crisis were light and sporadic, but over time the crises were more intense, occurring at approximate two month intervals with a duration of at least two days. The cri-sis incapacitated the patient from her socio-labor activities due to alteration in facial esthetics. Abdominal pain or respiratory alterations were never symptoms during the attacks. She reported having initiated the use of oral contraceptives for about nine years with no pause. She never got pregnant. There was no known history of angioedema in her family. The crises were not associated with the intake of any medication. The initial diagnostic hypotheses were made of common angioedema and hereditary angioedema (HAE). During the investigation, an idio-pathic thrombocitosis was discovered and started being monitored along with a hematologist. The gen-eral tests, except for an increase in platelet levels, were normal, as were the C4, C1q and C1 inhibitor (Chart 1). The inhibitor had been asked previously and always appeared normal. It was requested a discon-tinuation of oral contraceptives for possibly dealing with a case of HAE type III but also by
thrombocito-sis. After stopping the medication, the patient had no more angioedema crisis. She has been monitored for three years.
2. Female patient, 35 years, single, biomedical researcher, with a 12 years history of recurrent episodes of severe edema on the upper lip and face. Initially the attacks occurred twice a year however last year these became more serious, occurred fortnightly and with a duration of 4 to 5 days, including once requiring hospitalization in the Intensive Therapy Unit (Figures 1 and 2). The patient related the crisis to emotional stress and also reported a worsening of symptoms during menstruation. She also never became pregnant. The patient had been taking oral contraceptives for 12 years, but never associated it with the crisis of angioedema. She had previously used a large number of antihistamines, corticosteroids and adrenaline, without improvement. Her mother had similar episodes of angioedema for 28 years, but in the last eight years she did not have more attacks. Diagnostic hypotheses of common and hereditary angioedema were made and tests were requested for the diagnosis, during the inter-crisis and crisis period (Chart 1).
Since there was no change in the INHC1, it was thought to be a possible case of type III HAE, result-ing in the suspension of the oral contraceptive. The patient has subsequently been free of attacks, a period of 30 months.
3. Female patient, 26 years, single, student, with a history of the appearance two years ago of recurrent swellings on her face and in various other locations on
FIGURE1:
her body. She reported that the crisis were initially sparse however last year the frequency increased, occurring once or twice a month and preventing her normal activities. During these two years she had intense abdominal pain twice, along with facial swelling. The crisis did not respond to therapy with antihistamines and / or corticosteroids. She had used oral contraceptives for 10 years, and eventually other drugs, which she did not relate to episodes of facial swelling. The patient never fell pregnant. There was no family history of angioedema. The initial diagnos-tic hypotheses were made of common angioedema and hereditary angioedema. The examinations were normal between and during the crisis, including C1 and C4 inhibitor (Chart 1). Since there was no change in the inhibitor, the possibility of hereditary angioede-ma type III was considered. We opted for the suspen-sion of oral contraceptives and she experienced no further attacks, being monitored for 21 months.
DISCUSSION AND LITERATURE REVIEW
Angioedema is clinically characterized by sud-den swelling of the skin and / or mucous, including respiratory and gastrointestinal tracts, with limited duration of 2 to 3 days, not itchy, but with pain and variable burning sensations.1 In many patients, it is
associated with crisis of urticaria, taking part in this case of the clinical picture on the same disease. However, if the angioedema occurs alone, it’s classi-fied as a separate entity and is called angioedema without wheals, which may be acquired or hereditary.1
Hereditary angioedema (HAE) is a rare domi-nant Mendelian gene inheritance, affecting approxi-mately 1:50,000 people. 1 It is currently classified into three types (I, II and III), according to the deficiency or absence of C1 inhibitor (INHC1). In the first two types there is INHC1 deficiency, quantitative in HAE type I and qualitative in type II. In the type III the deficiency of INHC1 does not occur.2
The INHC1 is a regulatory protease of the classi-cal pathway of the complement system whose function is to inhibit the proteolytic activation of C2 and C4, coagulation factor XII (Hagemann factor) and the pro-duction of kallikrein, plasmin and bradykinin. Deficiency in INHC1 causes uncontrolled inflamma-tion consequent to the overproducinflamma-tion and accumula-tion of bradykinin, the major mediator of angioedema.3
The crises of HAE can be triggered by trauma, pressure, emotional stress and the use of medications, especially inhibitors of angiotensin-converting enzyme (ACE) and estrogens, which may induce and / or exacerbate quiescent disease in all types of HAE. 3 The crises of HAE are uncomfortable for the patient, but doesn’t offer risk of death, except when they involve the airways, which could result in asphyxia-tion.3All three types of HAE have the same incidence
of asphyxia and death.
Many patients also present bowel wall edema during the crises, which clinically results in episodes of severe and debilitating abdominal pain, sometimes the only symptom of HAE. Vomiting and alteration of the intestinal pace may also be exhibited, symptoms which often mimic an acute abdomen.3
In relation to pregnancy, patients with HAE usually improve, especially from the second quarter. The trauma of delivery does not precipitate the crisis, but these may recur after the first week of the puer-perium.3
The HAE type III was first reported in 2000 by Bork et al, affecting women without qualitative or quantitative INHC1 alteration.2The crises are related
to the use of estrogen and during pregnancy. In this article, we described three cases of patients with hereditary angioedema type III. All of them had a clin-ical feature of angioedema without wheals, with fre-quent disabling episodes affecting their social and lab-orative lives, involving mainly the face. Dosages of INHC1 and C4 were normal between and during the crisis (Chart 1).
It is known that estrogen has a role not yet fully understood in the crisis of HAE type III. In many cases, the estrogen initiated and / or exacerbated the crisis of angioedema, as with the patients described in this arti-cle.5 Binkley and Davis created the term
estrogen-dependent after observing angioedema conditions in women with high-leveled conditions of estrogen.6 FIGURE2:
There are reports of non-family cases, sporadic, that could present new genetic mutations, different to those already described so far and still unknown.10Of
the three patients described in this article, only one presented a known family history of angioedema (mother). Genetic tests that could classify patients with a genetic alteration were not performed due to the difficulty of such tests in our facilities.
Recently, Bork proposed a new classification of HAE, according to the latest genetic findings. According to this new classification, there were three types of HAE:
(a) with a genetic deficiency of INHC1 (HAE types I and II);
(b) with normal INHC1 (HAE type III) includ-ing those with two known mutations of the gene fac-tor XII (FXII-HAE) and those of unknown genetic cause (HAE-unknown).4
The HAE attacks begin during childhood and worsen at puberty but can occur at any age. The onset of symptoms in adulthood is significantly higher in patients with HAE type III.13
Symptoms of HAE type III are similar to other types of HAE: recurrent skin swelling, abdominal pain attacks, swelling of the tongue and pharynx. There are no associated wheals.13 The main clinical
and laboratorial differences with the HAE with INCH1 deficiency (types I and II) and normal INCH1 (type III) are in chart 2.
Bork suggested that the face would be the site most affected in these patients, especially the lips.12It
is observed that the clinical manifestations of HAE They also proposed a mutation in the androgen locus
of the gene that encodes the INHC1. Elevated estrogen levels are associated with increased levels of factor XII that, when activated, converts prekallikrein to kallikrein, and consequently produces a greater amount of bradykinin.7 Besides this, high levels of
estrogen during pregnancy or with the use of oral con-traceptives are associated with a reduction of INHC1.7
The inheritance pattern of HAE type III has been the subject of numerous studies and a source of discussion since the first reported cases. Initially, Bork et al suggested a dominant inheritance X-linked, because all affected patients were female.4Binkley and
Davis reported an Italian family with HAE type III that presented a dominant gene whose males were asymptomatic carriers of the anomaly.6,7 Bork et al
also reported the occurrence of the disease in a family in which three patients were male, suggesting a gene inheritance indeed, but not necessarily X-linked.8 In
this case, there could be another mutation, as is observed in other types of HAE, without the existence of cases previously reported in the same family. In 2006 Dewald G et al and Cichon et al identified two mutations in the FXII gene (decoder of the Hagemann factor) that would lead to a substitution of threonine to lysine (Thr309Lys) and another that would replace the threonine to arginine (Thr309Arg).9,10However, not
all families of patients with HAE type III would have these mutations. Besides these, several other muta-tions have been described over the past year, indicat-ing a genetic polymorphism that contributes to phe-notypic diversity of HAE type III.7,10-14
CHART1: Clinical features and laboratorial examinations of the patients
Initial age
Association with contraceptive
Association with pregnancy
Affected family members
Episodes of laryngeal edema
Response to corticosteroids and / or antihistamines
Hemogram
Quantitative and Qualitative INHC1
C4
1
26
Yes
-No
No
No
Thrombocytosis
Normal
Normal
3
24
Yes
-No
No
No
Normal
Normal
Normal
2
23
Yes
-Yes
Yes
No
Normal
Normal
type III are highly variable and it is believed that the penetration of the disease is low, since there are reports of symptoms emerging in seemingly asympto-matic female carriers of the genetic changes in the sev-enth decade of their lives.13 In addition, there are
reports of symptomatic patients with normal and / or low levels of estrogens, besides the manifestation of the disease in men.10
All patients described in this article began the crises in adulthood, affecting mainly the face, with lip swelling and eventually associated swelling of the tongue and larynx. Patient 1 still had abdominal pain associated with skin condition.
Laboratory tests are required for the diagnosis of HAE when there is a clinical suspicion and / or family history of angioedema. The serum C4 and INHC1 dosages are recommended (quantitative and qualitative). The C4 and INHC1 should also be evalu-ated in crises when the results are normal. There is no indication of dosing CH50 or C3.14Figure 3 shows the
algorithm diagnosis of HAE. If both the C4 and the quantitative INCH1 are low, then the diagnosis is compatible with Type I HAE. If the C4 is below nor-mal and the quantitative INCH1 is nornor-mal, it is sug-gested the dosage of qualitative INHC1; if it’s low, the diagnosis is compatible with HAE type II. All tests should be repeated on another occasion to confirm the diagnosis.14If both the C4 and the quantitative INCH1
are normal, types I and II can be excluded and the hypothesis of HAE type III should be considered. In this case, the repetition of the tests during the angioedema crisis is always recommended.14
In patients under 1 year old the laboratory tests are not reliable and should be repeated with greater age, because it may cause false positive results and / or false negative even when there are genetic alter-ations.14
The C4 and quantitative INHC1 dosages are routine examinations in large laboratories, but the qualitative assessment of C1, in our environment, is performed only in a few specialized laboratories.
So far the diagnosis of HAE type III is conduct-ed by clinical criteria, therefore there are no laborato-ry tests to confirm it.10 In cases of suspected genetic
mutation with the HAE and FXII, the diagnosis requires a confirmation of the mutation, reproducible only in research centers. In our patients, the absence of laboratory parameters, coupled with the clinical feature and immediate response to the removal of estrogen led to the diagnosis.10
The treatment of HAE consists of the manage-ment of the attacks and long-term prophylaxis. It is well recognized that corticosteroids, antihistamines and epinephrine are not useful.3,15
The therapeutic experience of this new type of HAE is limited because there are no well-controlled studies.10
Initially the use of estrogens (oral contracep-tives and hormone replacement therapy) must be sus-pended, as high levels of this hormone are related to angioedema crisis.
In the acute phase, the following medications can be used: concentrated INCH1, fresh frozen plas-ma, ecallantide and icatibant.15
CHART2:Some clinical characteristics that distinguish normal HAE with INHC1 from HAE with reduced
INHC1 - Bork modified, 2010
Patients have normal INHC1 activity
It mainly affects women
The incidence is lower in children aged under 10. The clinical symptoms begin in adulthood in most patients
There are more remission breaks in the course of the disease
Facial swelling, especially of the lips, is relatively more frequent
The tongue is considerably more affected
Many patients present only cutaneous angioedema and tongue swelling
Abdominal attacks are less frequent
Asphyxia can be preceded and caused by swelling of the tongue
In a study of seven patients with estrogen-dependent HAE who received concentrated dose of INHC1 during the angioedema crisis, six reported moderate or significant improvement of symptoms.13
Fresh frozen plasma is effective in the acute phase of classical types of HAE. There is a theoretical basis for using it also in HAE type III, especially if the use of concentrated INCH1 is not possible. 10 However, there is no evidence in the literature to jus-tify its usage.
The ecallantide is a potent and selective inhibitor of kallikrein which has been recently used successfully in the crises of the classical HAE.16
However, there are still no reports of its use for HAE type III.10
The icatibant, an antagonist of the bradykinin B2 receptor, has been shown to be effective in the treatment of episodes of HAE, including the
estrogen-Consider clinical features: angioedema without wheals, laryngeal edema, recurrent
episodes of abdominal pain and vomiting, positive family history
Serum dosages: C4, quantitative and qualitative INHC1 (if possible)
C4 and quantitative INHC1 low
Confirm with second dosage
If positive family history
HAE type I
Quantitative INHC1 normal
Reduced qualitative INHC1
HAE type II
HAE type III Low C4 and normal
or elevated quantitative INHC1
Quantitative examination of INHC1 and repeat C4
Normal C4 and INHC1
Confirm during the crisis
Evaluate other causes of C4 consumption
FIGURE3: Algorithm of diagnosis of hereditary angioedema (HAE)
dependent HAE, with the resolution of symptoms within 2-3 hours.17
Prophylactic therapy consists in the use of attenuated androgens, antifibrinolytic agents and progesterone. The attenuated androgens are the most effective drugs and well tolerated because they increase the levels of INHC1 and reduce the frequen-cy of crisis.3Danazol is the most frequently used drug
and can lead to remission of symptoms in patients with HAE- FXII.15Adverse effects such as
hepatotoxi-city and virilization are uncommon.3Tranexamic acid
suc-cessful use in a patient with estrogen-dependent HAE.15 Its use is indicated in cases with persistent
symptoms even after the suspension of estrogen.10
Attention should be paid to the higher incidence of thromboembolism during its use.
Pregnant women represent a problem because androgens and antifibrinolytic agents are contraindi-cated.3
Progesterone was used between 1 to 6 years in a study of eight patients with HAE FXII. Seven of them taked progesterone in the form of oral contra-ceptive and one pacient taked in the form of medrox-yprogesterone injections. All remained attacks free during the treatment.13
To sum up, there are several treatment options aiming the control of crisis for patients with HAE estrogen-dependent, but none confirmed with con-trolled studies. Most important, as an initial measure-ment, is the suspension of exogenous estrogen (oral contraceptives or hormone replacement therapy). Currently, during crises, the best treatment seems to be the concentrated INCH1, not available in Brazil. 10
The three patients described in this article showed a total improvement of the crisis only with the suspension of oral contraceptives. They had previ-ously used medications such as antihistamines, corti-costeroids and adrenaline, without success. Since the condition remains in remission, it is not necessary to administer any prophylactic drugs.
In conclusion, the HAE type III or estrogen-dependent disease is recent and rare, with a diagnosis based on the clinical chart, family history and in many cases, association with estrogen. The three cases reported in this article demonstrate it is a disease with a relatively simple diagnosis and treatment, which often goes unnoticed in our daily clinical practice. This disease when recognized and correctly diag-nosed leads to effective therapeutic measures institut-ing a vast improvement in the quality of life of patients, since it is commonly understood that angioedema causes great social and physical embar-rassment. ❑
How to cite this article: Miranda AR, Ue APF, Sabbag DV, Furlani WJ, Souza PK, Rotta O. Hereditary angioedema type III (estrogen-dependent) report of three cases and literature review. An Bras Dermatol. 2013;88(4):578-84.
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